A complex interplay among numerous biological and environmental factors govern both ethanol (EtOH) seeking and drinking behavior. Among these, genetics and stress certainly play prominent roles in shaping vulnerability and susceptibility for future problems with EtOH, as well as risk of developing alcoholism. While stress has been viewed as an important contributing factor to EtOH abuse and alcoholism, the interaction between stress and EtOH drinking behavior is not well understood. This is especially true when one considers the role/impact of stress on EtOH self-administration in the context of EtOH dependence. Chronic excessive consumption of EtOH can lead to the development of dependence, and repeated experience with associated withdrawal episodes may constitute a powerful motivational force that contributes to the perpetuation of EtOH use/abuse. Further, functional changes in brain/neuroendocrine stress and reward systems as a result of chronic EtOH exposure may render subjects not only more vulnerable to engage in excessive uncontrollable EtOH drinking, but also more susceptible to events (stress) that may trigger re-initiation of EtOH use after periods of abstinence (relapse). Unfortunately, little is known about the dynamics associated with the relationship between stress and EtOH consumption after dependence has been established. While a substantial emphasis of the existing NIAAA-supported "Stress, Anxiety and Alcohol Abuse" (WFUSM-INIA) Consortium is focused on elucidating the interaction of stress on EtOH consumption in various genetic mouse models, none of this work involves looking at the stress-EtOH relationship in dependent animals. The overall goal of this project is to utilize our established mouse model of EtOH dependence to investigate whether stress associated with repeated cycles of chronic EtOH exposure/withdrawal experience influences EtOH self-administration behavior, and whether such experience subsequently influences the ability of acute stress to modify EtOH seeking and drinking behavior. As such, this project not only fills a void in the literature related to EtOH dependence and stress, but importantly, it targets the major overarching theme of the WFUSM-INIA Consortium. Furthermore, the proposed work not only complements ongoing work in the Consortium, but it enhances the Consortium by expanding its focus to include the full spectrum of the addiction process, from use, to abuse, and to dependence. The overall goal of this proposal is to provide new information about the interaction between EtOH dependence, stress, and EtOH drinking behavior that is relevant to the WFUSM-IN1A Consortium, as well as the alcohol field in general.